Virus‐Based Nanoreactors with GALT Activity for Classic Galactosemia Therapy

ChemMedChem ◽  
2021 ◽  
Author(s):  
Pedro Gama ◽  
Ruben D. Cadena‐Nava ◽  
Karla Juarez‐Moreno ◽  
Javier Pérez‐Robles ◽  
Rafael Vazquez‐Duhalt
Keyword(s):  
Galt Activity ◽  
Classic Galactosemia

scholarly journals Current and Future Treatments for Classic Galactosemia

2021 ◽  
Vol 11 (2) ◽  
pp. 75 ◽  
Author(s):  
Britt Delnoy ◽  
Ana I. Coelho ◽  
Maria Estela Rubio-Gozalbo
Keyword(s):  
Standard Of Care ◽  
Type I ◽  
Therapeutic Approaches ◽  
Restricted Diet ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Classic Galactosemia ◽  
Pathogenic Factors ◽  
Future Treatments ◽  
Novel Therapeutic

Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.

scholarly journals Galactose-1-Phosphate Uridyltransferase Activities in Different Genotypes: A Retrospective Analysis of 927 Samples

2018 ◽  
Vol 3 (2) ◽  
pp. 222-230 ◽  
Author(s):  
Tatiana Yuzyuk ◽  
Andrew R Wilson ◽  
Rong Mao ◽  
Marzia Pasquali
Keyword(s):  
Dietary Intervention ◽  
Finite Mixture Models ◽  
Gene Analysis ◽  
Molecular Testing ◽  
Reference Ranges ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Classic Galactosemia ◽  
Galt Gene ◽  
Life Threatening

Abstract Background Classic galactosemia is an inherited disorder of galactose metabolism caused by the impaired activity of galactose-1-phosphate uridyltransferase (GALT). Untreated galactosemia is life-threatening; however, early dietary intervention prevents mortality and reduces morbidity associated with this disease. The diagnosis of galactosemia includes the measurement of GALT activity in red blood cells (RBC) and GALT gene analysis. In this study, we evaluate GALT activity in different genotypes using the results of combined biochemical and molecular testing in 927 samples. Methods GALT activity in RBC was measured by LC-MS/MS. The analysis of the GALT gene was performed by targeted gene analysis and/or full gene sequencing. Samples were assigned based on the presence of pathogenic (G) or Duarte 2 (D) variants, or their absence (Neg), to G/G, D/G, G/Neg, D/D, D/Neg, and Neg/Neg genotypes. Finite mixture models were applied to investigate distributions of GALT activities in these genotypes. The reference ranges were determined using the central 95% of values of GALT activities. Results The ranges of GALT activity in G/G, D/G, G/Neg, D/D, D/Neg, and Neg/Neg genotypes are 0.0 to 0.7 μmol·h−1 gHb−1, 3.1 to 7.8 μmol·h−1 gHb−1, 6.5 to 16.2 μmol·h−1 gHb−1, 6.4 to 16.5 μmol·h−1 gHb−1, 12.0 to 24.0 μmol·h−1 gHb−1, and 19.4 to 33.4 μmol·h−1 gHb−1, respectively. Conclusions The GALT activity ranges established in this study are in agreement with the expected impact of the genotype on the enzymatic activity. Molecular findings should be interpreted in view of biochemical results to confirm genotype–phenotype correlation.

scholarly journals Fluorinated Galactoses Inhibit Galactose-1-Phosphate Uridyltransferase and Metabolically Induce Galactosemia-like Phenotypes in HEK-293 Cells

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 607 ◽  
Author(s):  
Verena Janes ◽  
Simona Grabany ◽  
Julien Delbrouck ◽  
Stephane P. Vincent ◽  
Johannes Gottschalk ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
Surface Expression ◽  
Hek293 Cells ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Hek 293 ◽  
Classic Galactosemia ◽  
Developmental Impairment ◽  
The Unfolded Protein Response ◽  
Metabolic Induction

Genetic defects of human galactose-1-phosphate uridyltransferase (hGALT) and the partial loss of enzyme function result in an altered galactose metabolism with serious long-term developmental impairment of organs in classic galactosemia patients. In search for cellular pathomechanisms induced by the stressor galactose, we looked for ways to induce metabolically a galactosemia-like phenotype by hGALT inhibition in HEK293 cells. In kinetic studies, we provide evidence for 2-fluorinated galactose-1-phosphate (F-Gal-1-P) to competitively inhibit recombinant hGALT with a KI of 0.9 mM. Contrasting with hepatic cells, no alterations of N-glycoprofiles in MIG (metabolic induction of galactosemia)-HEK293 cells were revealed for an inducible secretory netrin-1 probe by MALDI-MS. Differential fluorescence-activated cell sorting demonstrated reduced surface expression of N-glycosylated CD109, EGFR, DPP4, and rhMUC1. Membrane raft proteomes exhibited dramatic alterations pointing to an affection of the unfolded protein response, and of targeted protein traffick. Most prominent, a negative regulation of oxidative stress was revealed presumably as a response to a NADPH pool depletion during reduction of Gal/F-Gal. Cellular perturbations induced by fluorinated galactoses in normal epithelial cells resemble proteomic changes revealed for galactosemic fibroblasts. In conclusion, the metabolic induction of galactosemia-like phenotypes in healthy epithelial/neuronal cells could support studies on the molecular pathomechanisms in classic galactosemia, in particular under conditions of low galactose stress and residual GALT activity.

scholarly journals Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia

2013 ◽  
Vol 36 (6) ◽  
pp. 1049-1061 ◽  
Author(s):  
Emily L. Ryan ◽  
Mary Ellen Lynch ◽  
Elles Taddeo ◽  
Tyler J. Gleason ◽  
Michael P. Epstein ◽  
...  
Keyword(s):  
School Age Children ◽  
School Age ◽  
Galt Activity ◽  
Classic Galactosemia

scholarly journals The Incidence and Clinical Presentations of Galactosemia in Fars province, South West of Iran

2014 ◽  
Vol 3 (1) ◽  
pp. 39-45
Author(s):  
Alieh Mirzaee ◽  
Narjes Pishva ◽  
Zohreh Karamizadeh ◽  
Shahnaz Purarian ◽  
Fariba Hemati ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Room Temperature ◽  
Fars Province ◽  
Poor Growth ◽  
Galt Activity ◽  
Classical Galactosemia ◽  
Blood Samples ◽  
Classic Galactosemia ◽  
South West ◽  
Clinical Presentations

Background: In this survey we studied the incidence and clinical presentations of  galactosemia in Fars province, in south west of Iran. Galactosemia is a rare genetic metabolic disorder ofgalactose. Its metabolism can be performed through 3 pathways. Although enzymes deficiencyof each of them can lead to galactose accumulation in plasma, the term galactosemia is specifically used for UDP-galactose uridyl transferase (GALT) deficiency. Classical galactosemia (G/G) is mostly manifested by poor growth, irritability, lethargy, vomiting, poor feeding, and jaundice.Material and method: 337000 newborns were screened for galactosemia by measuring total galactose level. Blood samples were collected from the heel on the Gauthriepaper, and thencalorimetric test with enzyme was performed to determine total galactose level. Blood galactoselevel below 4mg/dl was considered as normal and it was repeated if it was more than 4mg/dl in the first stage. The test was considered as abnormal if it was more than 5mg/dl, then blood samples were collected on filter paper and dried for 3-4 hours at room temperature and shipped frozen to laboratory for detection of GALT activity and galactose and galactose-1-phosphate.Results: From those who were gone for screening, 105 newborns had total galactose level more than 5mg/dl, among them, 37 patients had galactose level more than 15 mg/dl. Overall 12 cases were considered as classic galactosemia with an incidence rate of 1/28000, in Fars province.Conclusion: Although all of our patients were symptomatic and were admitted byhyperbilirubinemia before receiving the results, neonatal screening had an important role in the early diagnosis and management of this disease.

Hand fine motor control in classic galactosemia

2021 ◽  
Author(s):  
Jessica MacWilliams ◽  
Sneh Patel ◽  
Grace Carlock ◽  
Sarah Vest ◽  
Nancy L. Potter ◽  
...  
Keyword(s):  
Motor Control ◽  
Fine Motor ◽  
Fine Motor Control ◽  
Classic Galactosemia

scholarly journals Clinical, Biochemical and Molecular Profile of Variant Galactosemia in Children Detected by National Newborn Screening: A Pilot Study

2017 ◽  
Vol 51 (3) ◽  
Author(s):  
Sylvia Capistrano-Estrada ◽  
Daffodil M. Canson ◽  
Catherine Lynn T. Silao
Keyword(s):  
Newborn Screening ◽  
Screening Program ◽  
Molecular Profile ◽  
Molecular Characteristics ◽  
Molecular Testing ◽  
Variant Form ◽  
Limited Information ◽  
Coding Region ◽  
Total Blood ◽  
Galt Activity

Objective. The observed irregularities in the biochemical profile and the limited information on long-term outcomes among patients with Duarte variant (D/G) galactosemia have led to patient management variability. This study examined the molecular characteristics of Filipino patients with presumed variant galactosemia for confirmation of diagnosis. It also aimed to describe the corresponding biochemical, clinical and neurodevelopmental profiles in order to gain a better understanding of the patients with normal galactose metabolites in spite of low to absent GALT activity detected by the local newborn screening program. Methods. Thirteen (13) patients who were presumed to have a variant form of galactosemia by national newborn screening between 2002 and 2010, and who previously underwent physical and neurodevelopmental assessment were included in the study. Repeat clinical, ophthalmologic and neurodevelopmental evaluations were done upon recruitment of participants. Direct sequence analysis of the coding region of the GALT gene was conducted to determine the patients’ genotypes. Results. None of the patients’ genotypes were consistent with Duarte variant (D/G) galactosemia. Their genotypes reflect the normal total blood galactose levels in patients, but were inconsistent with the absent or trace GALT activity. Conclusion. Molecular testing for the entire cohort of presumed “variant” galactosemia Filipino patients will provide better profiling of this condition. Re-evaluation and assessment of the current guidelines used by national newborn screening in classifying variant galactosemia are recommended.

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